Periostat

CLINICAL PHARMACOLOGY

After oral administration, doxycycline hyclate is rapidly and nearly completely
absorbed from the gastrointestinal tract. Doxycycline is eliminated with a half-life
of approximately 18 hours by renal and fecal excretion of unchanged drug.

Mechanism of Action: Doxycycline has been shown to inhibit collagenase
activity in vitro.1 Additional studies have shown that doxycycline reduces the
elevated collagenase activity in the gingival crevicular fluid of patients with
adult periodontitis.2,3 The clinical significance of these findings is not known.

Microbiology: Doxycycline is a member of the tetracycline class of antibiotics.
The dosage of doxycycline achieved with this product during administration is
well below the concentration required to inhibit microorganisms commonly associated
with adult periodontitis. Clinical studies with this product demonstrated no
effect on total anaerobic and facultativebacteria in plaque samples from patients
administered this dose regimen for 9 to 18 months. This product should not
be used for reducing the numbers of or eliminating those microorganisms
associated with periodontitis.

Pharmacokinetics

The pharmacokinetics of doxycycline following oral administration of Periostat® (doxycycline hyclate)
were investigated in 4 volunteer studies involving 107 adults. Additionally,
doxycycline pharmacokinetics have been characterized in numerous scientific
publications.4 Pharmacokinetic parameters for Periostat® (doxycycline hyclate) following single
oral doses and at steady-state in healthy subjects are presented as follows:

Absorption: Doxycycline is well absorbed after oral administration.
In a single-dose study, concomitant administration of Periostat® (doxycycline hyclate) with a
1000 calorie, high-fat, high-protein meal which included dairy products, in
healthy volunteers, resulted in a decrease in the rate and extent of absorption
and delay in the time to maximum concentrations.

Distribution: Doxycycline is greater than 90% bound to plasma proteins. Its apparent volume of distribution is variously reported as between
52.6 and 134 L.4,6

Metabolism: Major metabolites of doxycycline have not been identified.
However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin
decrease the half-life of doxycycline.

Excretion: Doxycycline is excreted in the urine and feces as
unchanged drug. It is variously reported that between 29% and 55.4% of an administered
dose can be accounted for in the urine by 72 hours.5,6 Half-life averaged 18
hours in subjects receiving a single 20 mg doxycycline dose.

Special Populations

Geriatric: Doxycycline pharmacokinetics have not been evaluated
in geriatric patients.

Pediatric: Doxycycline pharmacokinetics have not been evaluated
in pediatric patients (See WARNINGSsection).

Gender: Doxycycline pharmacokinetics were compared in 9 men and
11 women under fed and fasted conditions. While female subjects had a higher
rate (Cmax) and extent of absorption (AUC), these differences are thought to
be due to differences in body weight/lean body mass. Differences in other pharmacokinetic
parameters were not significant.

Race: Differences in doxycycline pharmacokinetics among racial
groups have not been evaluated.

Renal Insufficiency: Studies have shown no significant difference
in serum half-life of doxycycline in patients with normal and severely impaired
renal function. Hemodialysis does not alter the half-life of doxycycline.

Hepatic Insufficiency: Doxycycline pharmacokinetics have not
been evaluated in patients with hepatic insufficiency.

Clinical Study

In a randomized, multi-centered, double-blind, 9-month Phase 3 study involving
190 adult patients with periodontal disease [at least two probing sites per
quadrant of between 5 and 9 mm pocket depth (PD) and attachment level (ALv)],
the effects of oral administration of 20 mg twice a day of doxycycline hyclate
(using a bioequivalent capsule formulation) plus scaling and root planing (SRP)
were compared to placebo control plus SRP. Both treatment groups were administered
a course of scaling and root planing in 2 quadrants at Baseline. Measurements
of ALv, PD and bleeding-on-probing (BOP) were obtained at Baseline, 3, 6, and
9 months from each site about each tooth in the two quadrants that received
SRP using the UNC-15 manual probe. Each tooth site was categorized into one
of three strata based on Baseline PD: 0-3 mm (no disease), 4-6 mm (mild/moderate
disease), ≥ 7 mm (severe disease). For each stratum and treatment group, the
following were calculated at month 3, 6, and 9: mean change in ALv from baseline,
mean change in PD from baseline, mean percentage of tooth sites per patient
exhibiting attachment loss of ≥ 2 mm from baseline, and percentage of tooth
sites with bleeding on probing. The results are summarized in the following
table.